The major goal of this research project is to identify and characterize genes involved in the pathogenesis of human kidney cancer. Our major accomplishments this year are: 1. We demonstrated that mutations in the MET proto- oncogene are responsible for a recently recognized inherited form of kidney cancer, hereditary papillary renal carcinoma (HPCR). In contrast to our previous studies with the von Hippel-Lindau disease gene, mutations in the MET proto-oncogene were all missense, and were located in the catalytic domain of the protein. Mutations in the MET proto-oncogene were detected in 6/7 HPRC families, and in a subset of sporadic papillary renal carcinomas. 2. We demonstrated that the mutations in MET produced a gain-of- function. The mutations in MET detected in patients with HPRC and sporadic tumors produced malignant transformation of NIH 3T3 cells. Constitutive phosphorylation of the MET protein was demonstrated in mouse cells transfected with mutant MET genes. 3. Some of the mutations detected in MET were located in residues homologous to those mutated in other receptor tyrosine kinases, RET and KIT. These results suggest that we have identified residues of the catalytic domain common to several receptor tyrosine kinases that in mutant form produce disease. 4. We have identified another distinct inherited form of renal neoplasia. So far, we have identified 5 families with multiple members affected with renal oncocytoma. Affected individuals have multiple, bilateral renal oncocytomas.